KRAS mutations in non-small-cell lung cancer and colorectal cancer: Implications for EGFR-targeted therapies

M. K H Maus, P. P. Grimminger, Philip Mack, S. H. Astrow, C. Stephens, G. Zeger, J. Hsiang, J. Brabender, M. Friedrich, H. Alakus, A. H. Hölscher, Primo N Lara, K. D. Danenberg, H. J. Lenz, David R Gandara

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Background: KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and methods: Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined. Results: KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<. 0.001), smoking-associated G>T transversions (73% versus 27%; p<. 0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<. 0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion: In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.

Original languageEnglish (US)
Pages (from-to)163-167
Number of pages5
JournalLung Cancer
Volume83
Issue number2
DOIs
StatePublished - Feb 2014

    Fingerprint

Keywords

  • Colorectal cancer (CRC)
  • EGFR-targeted therapy
  • KRAS mutations
  • Molecular genetics
  • Non-small-cell lung cancer (NSCLC)
  • Personalized medicine
  • Predictive biomarkers

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Maus, M. K. H., Grimminger, P. P., Mack, P., Astrow, S. H., Stephens, C., Zeger, G., Hsiang, J., Brabender, J., Friedrich, M., Alakus, H., Hölscher, A. H., Lara, P. N., Danenberg, K. D., Lenz, H. J., & Gandara, D. R. (2014). KRAS mutations in non-small-cell lung cancer and colorectal cancer: Implications for EGFR-targeted therapies. Lung Cancer, 83(2), 163-167. https://doi.org/10.1016/j.lungcan.2013.11.010